Diagnostic systems in psychiatry have limitations resulting in classifications that are heterogeneous, lack clear boundaries, and inadequately match biological constructs. Clinical phenotypes such as schizophrenia (SZ)-spectrum diagnoses, when applied in genetic analyses, result in inconsistent findings, despite some interesting leads. Endophenotypes are specific deficits in brain anatomy and/or function interposed between overt clinical disease and aberrant genes. Such measures provide more direct clues to genetic underpinnings than do clinical syndromes because they are closer in the etiological chain to the primary constitutional deviations resulting in disease. The current application responds to the need for endophenotypes in two important ways. First, we will identify in SZ the critical deviation at the level of brain function accounting for their antisaccade abnormalities, a promising and replicated behavioral endophenotype for this illness. Second, we will determine whether biological relatives of SZ (SZREL) manifest the same deviations in brain functioning as the SZ. This project will address a major question about SZ with implications for models of pathophysiology, clinical diagnostic nosology, and genetics. A common anomaly in brain function in SZ is disruption of prefrontal cortex (PFC). An inability to inhibit behavioral responses is an important manifestation of PFC pathology, an abnormality that can be quantified by the inability to inhibit reflexive glances to peripheral targets during antisaccade tasks. SZ and SZREL have high antisaccade error rates suggesting that anti-performance indexes a constitutional abnormality of liability for this illness. Demonstrating a relationship between SZ and anti-performance is an important step toward understanding the essential neuropathology and genetics of this illness. Clarifying how SZ-related neuropathology causes increased anti-errors requires studying the neural correlates of sub- processes necessary to enact this behavior. The present project will address this specific issue, and the results will yield a precise measure of failed neural control accounting for poor anti-performance among SZ and SZREL. Animal research indicates that neural bias signals are crucial for enabling successful inhibition on an anti-trial. Whether reduced or atypical preparatory activities in sensory or motor areas account for SZ and SZREL behavioral regulation difficulties during anti-tasks is uncertain. The proposed work, therefore, will address a fundamentally important question in the clinical neuroscience of SZ. This research requires the use of a novel paradigm, the use of high temporal resolution brain measurement technology (multichannel EEG), access to large SZ and SZREL samples, and collaboration between investigators with complimentary knowledge of this research area. The present project meets these requirements. PUBLIC HEALTH RELEVANCE People with schizophrenia have problems with inhibition which can be predicted by changes in brain activity. The patterns of activity in healthy subjects involve a distinct balance between increased activity in regions that help prepare a correct response and decreased activity in regions supporting competing processes, a pattern will be probed using measurement of brain activity via EEG and a novel antisaccade paradigm. It is expected this pattern will be disrupted in people with schizophrenia and their relatives.